3-(Amino-or aminoalkyl) pyridinone derivatives and their use for the treatment of HIV related diseases

ABSTRACT

3-(amino- or aminoalkyl) pyridinone derivatives having the formula (1)  
                 
 
     wherein Q, X, Y, and R 3 -R 6  are as defined, which derivatives are useful for the treatment of HIV related diseases.

[0001] The present invention is concerned with 3-(amino- or aminoalkyl) pyridinone derivatives which inhibit the reverse transcriptase of the Human Immunodeficiency Virus (HIV).

[0002] It relates moreover to the use of such compounds for treating HIV-related diseases.

[0003] Furthermore it relates to a process for the preparation of these compounds.

[0004] It is known that some pyrimidinone and pyridinone derivatives inhibit HIV reverse transcriptase.

[0005] In particular, derivatives from 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) are well known for their HIV1 reverse transcriptase inhibitory properties.

[0006] European Patent Application EP-0 462 800 (Merck and Company Inc.) discloses pyridinones being substituted on position 3 with an aryl or heterocyclic group, linked to the pyridinone ring through a chain.

[0007] Unfortunately, strains resistant to these compounds appeared Thus, their use in therapeutical treatments is questionable.

[0008] 4-aryl-thio-pyridinones have been more recently disclosed by DOLLE et al. (1995, J. Med. Chem., 38, 4679-4686), and in the corresponding PCT Patent Application WO 97/05 113.

[0009] However, their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains.

[0010] The most active thio pyridinones disclosed therein have a 50% inhibitory concentration of virus multiplication (IC₅₀ ) for nevirapine resistant strains of about 260 nM.

[0011] The inventors have found a new pyridinone derivative family which show better HIV inhibitory properties.

[0012] They have moreover found a new process for obtaining these compounds.

[0013] The present invention relates to compounds having the following general formula I.

[0014] wherein

[0015] Q represents —NR₁R₂ or —R₀NR₁R₂ wherein:

[0016] R₀ represents C₁₋₆ alkanediyl;

[0017] R₁ and R₂ each independently represent C₁₋₆alkyl or C₃₋₆alkenyl; said C₁₋₆alkyl and C₃₋₆alkenyl may be substituted with one, two or three substituents selected from hydroxy, C₁₋₄alkyloxy, C₁₋₄alkylthio, aryloxy, arylthio, amino, mono- or di(C₁₋₄alkyl)amino and aryl; or

[0018] R₁ and R₂ taken together may form a bivalent radical —R₁-R₂— wherein —R₁-R₂— represents —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—NR₇—(CH₂)₂, —(CH₂)₂—CH(NHR₇)—(CH₂)₂— or —(CH₂)_(n), wherein R₇ represents hydrogen or C₁₋₄alkyl and n represents 2, 3, 4, 5 or 6;

[0019] R₃ represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C₁₋₄-alkyl, C₁₋₄alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl,

[0020] R₄ and R₅ each independently represent hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl, C₁₋₄alkoxy, C₁₋₄alkyloxy, C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl) amino, formyl, C₁₋₄alkylcarbonyl, carboxyl, C₁₋₄ alkyloxycarbonyl, or C₁₋₄alkylaminocarbonyl; wherein C₁₋₆alkyl and C₃₋₆alkenyl may be substituted with one, two or three substituents selected from hydroxy, C₁₋₄alkyloxy, C₁₋₄alkyl thio, aryloxy, arylthio, amino, mono- or di(C₁₋₄alkyl)amino and aryl; or

[0021] R₄ and R₅ taken together form a bivalent radical of formula —R₄-R₅— wherein —R₄-R₅— represents —CH═CH—CH═CH— or —(CH₂)_(t)—, wherein t represents 3 or 4;

[0022] R₆ represents hydrogen, hydroxy, C₁₋₄alkyloxy, C₁₋₆alkyl, C₃₋₆alkenyl, aryl, C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino or alkylaryl;

[0023] Y represents O or S;

[0024] X represents a radical of formula:

—(CH₂)_(p)—

—(CH₂)_(q)—Z—(CH₂)_(r)—

[0025] or

—CO—

[0026] wherein p represents 1, 2, 3, 4 or 5;

[0027] q represents 0, 1, 2, 3, 4 or 5;

[0028] r represents 0, 1, 2 or 3;

[0029] Z represents NR₈, C(═O), CHOH, CHNR₈R₉; CF₂, O, S or CH═CH; wherein R₈ and R₉ each independently represent hydrogen or C₁₋₄ alkyl;

[0030] or N-oxides, stereochemically isomeric forms or a pharmaceutically acceptable addition salts thereof.

[0031] As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C₁₋₄-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like; C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higher homologues thereof containing 5 to 6 carbon atoms such as, for example, pentyl, hexyl or the like; C₃₋₆alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C₃₋₆alkenyl being connected to a nitrogen atom preferably is saturated; C₁₋₆-alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term <<C(═O)>> refers to a carbonyl group. Aryl is phenyl or phenyl substituted with one, two or three substituents selected from C₁₋₄alkyl, C₁₋₄alkyloxy, halo and trifluoromethyl,

[0032] Preferred compounds according to the present invention are those in which X represents —CH₂— or C (═O) and R₃ represents a phenyl group, substituted with two methyl groups, and the most preferred of them are those wherein R₃ represents a phenyl group substituted, in each meta position, with two methyl groups.

[0033] Preferably, in the compounds according to the present invention, R₁ and R₂ represent each a methyl group, R₄ represents an ethyl group, R₅ represents a methyl group and/or R₆ represents a hydrogen atom.

[0034] The most preferred compound of this invention is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

[0035] The compounds in which X is —CH₂—, R₃ represents a phenyl group optionally substituted, Y represents O and R₆ represents a hydrogen atom can be obtained by the general process represented on FIG. 1.

[0036] This first process comprises the following steps:

[0037] a) reacting a pyridine (2), substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, resulting in a lithiated derivate (3) of the said pyridine.

[0038] b) transforming the lithiated derivate (3) into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide.

[0039] c) obtaining the pyridinone (4) by reacting the organocopper reagent with optionally substituted benzyl halide.

[0040] d) hydrolysing the protected pyridinone (4) and obtaining the deprotected pyridinone (5).

[0041] e) substituting the 3-amine group of the pyridinone (5) and obtaining the pyridinone (6).

[0042] This first process is summarized in the reaction Scheme I hereinafter:

[0043] In this process R₁₀ and R₁₁ represent independently C₁-C₆ alkyl. In a preferred embodiment, R₁₀ is a methyl group and R₁₁ is a tert-butyl group.

[0044] The C₁-C₆ alkyllithium, reacted with the pyridine(2) can be a n-butyllithium.

[0045] The optionally substituted benzyl halide used in the step c) is preferably benzyl bromide.

[0046] The hydrolysis of the protected pyridinone(4), resulting in its deprotection, is advantageously obtained by adding hydrochloric acid to the pyridinone(4) and refluxing the mixture.

[0047] In a preferred embodiment, the amino group in position 3 of the pyridinone ring, deprotected during the step (d) is substituted by alkylation, by the Eschweiler-Clarke reaction.

[0048] Compounds wherein X represents —(CH₂)_(q)—Z—(CH₂)_(r)—, Y represents O, R₃ is an optionally substituted phenyl group and R₆ is an hydrogen atom can be obtained by a similar process.

[0049] Compounds wherein X represents C (═O), or —CH₂—, Y represents O, R₃ is an optionally substituted phenyl group and R₆ is an hydrogen atom can be obtained by a second process.

[0050] In this second process, the lithiated derivative (3) is reacted with an optionally substituted benzaldehyde, resulting in the intermediates of formula (7).

[0051] The intermediate (7) is oxidized to intermediate (8).

[0052] The intermediate (8) is thereafter deprotected by hydrolysis, as in the first process, resulting in the pyridinone (9) of general formula I.

[0053] This second process is summarized in the reaction scheme II hereinafter.

[0054] Preferably the oxidation of the intermediate (7) is performed in the presence of manganese dioxide.

[0055] The intermediate (7) can also be transformed into corresponding ester (10) wherein R₁₂ represents a C₁-C₄ alkyl group whose hydrogenolysis provides pyridinone(4) in better yields. Preferably, the ester (10) wherein R₁₂ is CH₃ is prepared by treatment of intermediate (7) with acetic anhydride. Subsequently hydrogenolysis is performed under hydrogen atmosphere and in the presence of a catalyst, especially 30% paladized charcoal. This process is summarized in the reaction scheme III

[0056] Other compounds of general formula I, and wherein X is (CH₂)_(p) or (CH₂)_(q)—Z—(CH₂)_(r) or C(═O), and R₃ is other than phenyl and R₆ is other than hydrogen can be obtained by these processes, appropriately adapted by the man skilled in the art.

[0057] The compounds according to the present invention, in which X is S can be obtained by the process described in the article of DOLLE et al. (1995, previously cited) or in the corresponding patent application WO 97/05 113, the contents of which are included in the present application.

[0058] The compounds can also be obtained by other processes known by the man skilled in the art.

[0059] The present invention relates moreover to the intermediates of the processes hereabove disclosed. In particular it relates to the lithiated derivative of formula (3).

[0060] The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, and in particular HIV-1 reverse transcriptase and the prevention or treatment of infection by the human immuno deficiency virus (HIV) and of HIV-related diseases, such as AIDS.

[0061] For these purposes, the compounds of the present invention may be administered orally, parenterally (including sub-cutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tectoniques), by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.

[0062] Thus, another object of the present invention is a method, and a pharmaceutical composition for treating HIV related diseases, HIV infection, and in particular AIDS.

[0063] The invention relates also to these compounds for use as medecine and to their use for the manufacture of a medecine for the treatment of HIV related diseases, HIV infection, and in particular AIDS.

[0064] These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectable preparations, or suppositories.

[0065] The present invention is illustrated without being limited by the following examples.

EXAMPLES Example 1 Preparation of 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one

[0066] 1) 5-Ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine

[0067] This compound has been prepared as indicated by DOLLE et al. (1997, Tetrahedron, vol.53, n°37, 12.505-12.524). The content of this article is hereby incorporated by reference.

[0068] 3.68 g of 3-Amino-5-ethyl-2-methoxy-6-methylpyridine (22.14 mmol), obtained as indicated by HOFFMAN et al. (1993, J. Med. Chem., 36, 953-966), was dissolved in a mixture of dichloromethane (260 ml) and triethylamine (3.39 ml). The mixture was cooled at 0° C. and 3.00 ml of trimethylacetyl chloride was added dropwise. The solution was stirred at 0° C. for 15 min. and then washed with 100 ml water. The aqueous layer was extracted with 3×200 ml dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluant to provide the 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5.31g; 96%). Elemental analysis calculated for C₁₄H₂₂N₂O₂; C, 67.17. H, 8.86; N, 11.19; 0, 12.78; found : C, 67.11; H. 8.56; N, 10.91; O, 12.67.

[0069] 2)4-(3,5-Dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine

[0070] i) By Lithiation of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine:

[0071] 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine and 3,5-dimethylbenzyl bromide were dried in the presence of phosphorus pentoxide under vacuum at room temperature during 24 hours. Copper iodide (Cu^(I)I) was dried in the presence of phosphorus pentoxide under vacuum at 50° C. for 24 hours. 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (1.06 g) and freshly distilled tetramethylethylenediamine (TMEDA) (2.24 mL) were dissolved in dry tetrahydrofuran (THF) (26 mL) and the mixture was cooled at −78° C. under a nitrogen atmosphere. n-Butyllithium (1.6 M in hexane, 9.26 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C.

[0072] Cu^(I)I: dimethyl sulfide complex, prepared by adding dimethylsulfide (14 mL) to a suspension of copper iodide (2.82 g) in dry THF (52 ml) at −78° C. under N₂ atmosphere, was then added dropwise to the mixture at −78° C. The mixture was stirred at 0° C. for 30 min and cooled again at −78° C. to allow the addition of 3,5-dimethylbenzyl bromide (3.81 g) dissolved in THF (4 mL). The resulting mixture was stirred at 0° C. for 3 hours and at room temperature for 12 hours. 16 mL of water and 20 mL of 28% aqueous ammonium hydroxide were added. The aqueous layer was extracted with 3×80 mL of ether. The combined organic layers were washed with 40 mL of brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using cyclohexane-ethyl acetate (1:0 to 8:2) as eluant giving 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (577 mg, 37%) mp 138-139° C.

[0073] ii) By hydrogenolysis of ±(5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-(3,5-dimethylphenyl)-methyl Acetate

[0074] (+, −) (5-Ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-(3,5-dimethylphenyl)-methylacetate

[0075] 8.34 g of (+, −)-(3,5-dimethylphenyl)-(5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-methanol, prepared as described below, was dissolved in pyridine (200 mL) and added to acetic anhydride (10.24 mL), and the solution was stirred for 1.5 h at room temperature and for 60 h at 60° C. An additional 10.24 mL of acetic anhydride (108.51 mmol) was added and heating was continued at 60° C. for 24 h. The pyridine was evaporated under reduced pressure and the residue was taken up in 500 mL of ethyl acetate. The organic layer was washed with 170 mL of an aqueous saturated sodium bicarbonate solution, 170 mL of water and 170 mL of brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using dichloromethane-ethanol (1:0 to 95:5) to give the titled compound (8.78 g, 95%) mp 70-71° C.

[0076] A mixture of this compound (850 mg) and Pd-C (30%, 850 mg) in acetic acid-water-dioxane (42.5 mL, 2:1:2, v/v/v) was stirred at room temperature for 24 hours under 10 atm of hydrogen. The catalyst was removed by filtration and washed with ethanol. The solvent of the combined filtrates was evaporated under reduced pressure giving 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (726 mg, 99%) which was identical to the compound as prepared in example 1.2.i).

[0077] 3) 3-Amino4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one

[0078] 3M aqueous hydrochloric acid (150 mL) was added to a suspension of 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (2.36 g) in water (300 mL). The mixture was refluxed for 3.5 h and then stirred at room temperature for 12 h. The solution was basified by adding concentrated ammonium hydroxyde and was extracted with 3×800 mL ethyl acetate. The combined organic layers were washed with 110 mL brine, dried over magnesium sulfate and concentrated under reduced pressure giving 3-amino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one. (1.79 g, 100%). mp 204-205° C.

[0079] 4) 3-Dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2-(1H)-one

[0080] To a stirred solution of 3-amino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one (200 mg) and 37% of aqueous formaldehyde (0.60 mL) in 5 mL of acetonitrile was added 139 mg of sodium cyanoborohydride. Glacial acetic acid (0.07 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. An additional 0.07 mL of glacial acetic acid was added, and stirring was continued for 30 minutes. The solvent was evaporated and 15 mL ether were added to the resulting residue. The organic layer was washed with 3×30 mL 1N aqueous potassium hydroxide and 3 mL brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-dimethylamino4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one (200 mg, 91%) mp 229-230° C.

Example 2

[0081] 1) Biological Activity of the Compound According to Example 1

[0082] 1. Material and Methods

[0083] The antiviral activity, the expression and purification of the recombinant HIV-RT enzyme, the reverse transcriptase activities and the inhibition of RT were evaluated as described in WO 97/05 113.

[0084] The retrovirucidal effect and the reverse transcription were measured as described hereinafter.

[0085] 1.1. Retrovirucidal Effect

[0086] HIV-1 viral suspensions were obtained by coculture of MT4 cells and H9 cells chronically infected by HIV-I_(Lai) isolate. 200 μl of a cell supernatant containing viral particles (HIV-I_(Lai): 100 TCID₅₀) were incubated at room temperature with various concentrations of different inhibitors. After 3 hours, virions were washed through 0.02 μm anopore membrane in 1.5 mL Vectaspin tube (Whatman) for 10 minutes at 5 000 g. Each of the three subsequent washes was performed in the same conditions after the viral concentrate was refilled with 500 μL of RPMI medium. Then, the viral concentrate was readjusted to the initial volume with RPMI plus 10% foetal calf serum (FCS). The residual infectivity was assayed on P4 cells as described by CHARNEAU et al.. (1994, J. Mol. Biol., 241, 651-662). Briefly, P4 cells were plated using 100 μL of DMEM medium plus 10% FCS in 96 plate multi-wells at 20×10⁵ cells per mL. After overnight incubation at 37° C., the supernatant was discarded and the viral preparation (200 μL) was added. One day later the wells were washed three times in PBS. Each well was refilled with 200 μL of a reaction buffer containing 50 mM Tris-HCl pH 8.5, 100 mM 2-mercaptoethanol, 0.05% Triton X-100 and 5 mM 4-methylumbelliferyl β-D-galactopyranoside (MUG). After 3 hours at 37° C., the level of the reaction was measured in a fluorescence microplate reader.

[0087] 1.2) Reverse Transcription

[0088] The plasmid pAV4 containing the 50-997 HIV-1 nucleotide fragment (MAL strain) in pSP64, under the control of the bacteriophage T7 promoter was a kind gift from Dr. J. L. DARLIX (INSERM-Lyon, France). E. coli HB 101 recA⁻ was used for plasmid amplification. After digestion of this clone with PstI and in vitro transcription using T7 RNA polymerase, a HIV-1 genomic RNA fragment starting at position +50 of the MAL sequence was obtained. In vitro transcription using T7 RNA polymerase as performed as follows. Three μg of linearized plasmid DNA were transcribed in 100 μL of 40 mM Tris -HCl pH 8.0, 8 mM MgCl₂, 10 mM spermidine, 25 mM NaCl, 10 mM dithiothreitol, 0.5 mM of each ribonucleoside triphosphate, with 100 units of T7 RNA polymerase and in the presence of 20 units of human placenta ribonuclease inhibitor, for 2 hours at 37° C. After treatment with 12 units of Rnase-free Dnase I (for 10 minutes at 37° C.), the RNA transcripts were extracted with 1 volume of phenol/chloroform/isoamyl alcohol (24:24:1) and with chloroform and precipitated in 2.5 volumes of ethanol and 0.3 M ammonium acetate (pH 5.5).

[0089] Reverse transcription was performed in a total volume of 50 μL containing 50 mM Tris-HCl pH 8.0, 6 mM MgCl₂, 2 mM dithiothreitol, 12 mM NaCl, 150 nM HIV-1 RNA, and either 200 nM of a synthetic oligodeoxynucleotide primer (18-mer ODN) complementary to the PBS of HIV-1 RNA, or 200 nM tRNA^(Lys3). When the 18-mer ODN was used as primer, incubation was carried out at 37° C. with the template and 300 nM RT. After 30 minutes, 10 μCi [α-³²P]dGTP (3000 Ci/mmol) and 0.1 mM of each dNTP were added and the incubation proceeded for 30 minutes at 37° C. With tRNA^(LYS3) as primer, the same conditions were used except that tRNA and RNA were prehybridized by heating for 2 minutes at 90° C. and then slowly cooled. Samples were extracted with phenol-chloroform and collected by ethanol precipitation. Reaction products were analyzed on 8% polyacrylamide-TBE (90 mM Tris pH 8.3, 90 mM borate, 2 mM EDTA)-7 M urea gels.

RESULTS

[0090] The antiviral activity of the compounds according to example 1 has been tested on various strains.

[0091] On HIV-LAI wild type this compound shows the following activities: IC50=0.2 nM; CC50>10⁵ nM (S.I.>33.333).

[0092] On an HIV-1 novirapine resistant strain the activities of the compound of example 1 are as follows:

[0093] IC₅₀>10⁴ nM

[0094] CC₅₀>10⁴ nM

[0095] The compound of example 1 has been also tested on various HIV strains and primary cell cultures. The table 1 illustrates the activity of this compound on these strains.

[0096] The retrovirucidal effect of the compound according to example 1 has been tested. Table 2 illustrates this effect at various doses of this compound.

[0097] The IC₅₀ of the compound of example 1 for the inhibition of the reverse transcriptase is 20 nM. TABLE 1 Anti HIV-1 activity of the compound of example 1 on various HIV strains and primary cell cultures IC₅₀(nM)/CC₅₀(nM) HIV-1 Bal/ HIV-1 HIV-1 HIV-1 HIV-2 D Mono/ IIIIB/ AZTres./ IIIB/ 194/ macro- Compound MT4 MT4 PBMC PBMC phages Example 1 2.4/ 0.2/>1000 0.58/ >1000/>1000 0.004/>1000 >1000 >1000

[0098] TABLE 2 Inhibition of infectivity of the compound of example 1 Dosage of compound of example 1 % inhibition of infectivity 10 nM 26% 100 nM 46% 1 μm 83% 10 μm 99%

Example 3 Other 3-(amino- or aminoalkyl) Pyridinone Derivatives and Their Retrovirucidal Activity Against Two Different HIV-1 Strains

[0099] 3.1 Compounds

[0100] Further compounds according to the general formula (I) (compounds n°1-25, 27-108, 110-125, 127-145 and 147-203) as well as four intermediate compounds used for synthesis (compounds n°26, 109, 126 and 146) have been synthesized and are listed in table 3 below.

[0101] The meaning of each of the groups Y, Q and R3 - R6 is defined for every exemplified pyridinone derivative.

[0102] 3.2 Retrovirucidal Effect

[0103] The retrovirucidal effect of each pyridinone derivative listed in table 3 has been assayed according to the teachings of example 2, excepted that the anti-viral effect has been tested on the two following HIV-1 strains:

[0104] a) HIV-1 strain IIIB (see example 2);

[0105] b) HIV-1 strain 103 N which is a mutant strain bearing a point mutation in the reverse transcriptase gene leading to an enzyme wherein the initial Lys-103 residue is replaced for a Asn residue.

[0106] HIV-1 103N strain exhibits resistance to the reverse transcriptase inhibitor TIBO R82913 (BALZARINI J. et al. 1993, Virology, 192: 246-253). The HIV-1 103 N strain has also been described by SAHLBERG et al.,(1998, Antiviral Res., 37 (3): ASS) and BALZARiNI et al. (1996, Antimicrobial Agents and Chemotherapy, 40 (6): 1454-1466).

[0107] The results are expressed as pIC₅₀ (pIC₅₀=−log IC₅₀), of every of compound as regards to each of the HIV-1 strains IIIB and 103N. Thus, the pIC50 value of compound n°1 as regards to HIV-1 IIIB being 7,6999, the IC₅₀ can be directly deduced as being equal to 10^(−7.6999)M.

[0108] Such high retrovirucidal activities had never been observed previously when using prior art reverse transcriptase inhibitors.

[0109] Consequently, the novel pyridinone derivatives according to the present invention are of a high therapeutical value against HIV related diseases, particularly against HIV-1 related diseases. TABLE 3 HIV1 pIC50 strain strain Y Q R3 R4 R5 R6 IIIB 103N 1 O NH2

Chemistry 4 Et Me H 7.699 6.671 2 O NH2

3,5-Dimethylbenzyl Et Me H 6.612 6.64 3 O NMe2

3,5-Dimethylbenzyl Et Me H 8.004 7.438 4 O

Chemistry 33

3,5-Dimethylbenzyl Et Me H 5.094 <4 5 O NH2

3,5-Dimethylbenzyl Et Me H 6.621 5.636 6 O NH2

Chemistry 52 Et Me H 5.795 5.026 7 O NH2

Chemistry 58 Et Me H <4 <4 8 O NH2

4-Methylbenzyl Et Me H 4.373 4.39 9 O NH2

3-Methylbenzyl Et Me H 5.373 5.103 10 O NMe2

Chemistry 82 Et Me H 6.241 4.389 11 O NMe2

3,5-Dimethylbenzyl Et Me Me 7.215 6.094 12 O NEt2

3,5-Dimethylbenzyl Et Me H 8.022 6.363 13 O NMe2

3-Methylbenzyl Et Me H 8.824 7.622 14 O NMe2

2-Methylbenzyl Et Me H 7.676 5.849 15 O NH2

3,5-Dimethylbenzyl H H H <4.17 4.138 16 O NMe2

3,5-Dimethylbenzyl H H H 5.061 4.401 17 O N(n-Pr)2

3,5-Dimethylbenzyl Et Me H 6.285 4.379 18 O NMe2

4-Methylbenyl Et Me H 6.454 4.895 19 O NMe2

3,4-Dimethylbenzyl Et Me H 7.447 5.947 20 O NMe2

2,3-Dimethylbenzyl Et Me H 6.926 5.585 21 O NMe2

Benzyl Et Me H 8.409 6.65 22 O NMe2

3,5-Dimethylbenzyl Et Me Benzyl 4.603 <4 23 O NMe2

3,5-Dimethlylbenzyl Et Me

Chemistry 163 5.254 <4 24 O

Chemistry 165

3,5-Dimethylbenzyl Et Me H 4.262 <4 25 O

Chemistry 171

3,5-Dimethylbenzyl Et Me H <4 4.259 26 O

Chemistry 177

3,5-Dimethylbenzoyl Et Me H 27 O NH2

3,5-Dimethylbenzyl Me Et H 5.949 5.098 28 O NMe2

3,5-Dimethylbenzyl Me Et H 8.032 6.943 29 O NHCH2Ph

3,5-Dimethylbenzyl Et Me H 6.555 5.496 30 O

Piperidin-1-yl

3,5-Dimethylbenzyl Et Me H 6.214 4.224 31 O NH2

2,4-Dimethylbenzyl Et Me H <4 <4 32 O NH2

3,5-Dimethylbenzyl Me Me H 6.104 <5 33 O NMe2

3,5-Dimethylbenzyl Me Me H 8.42 6.285 34 O NMe2

2,4-Dimethylbenzoyl Et Me H 5.019 <4 35 O NMe2

3,5-Dimethylbenzyl Et Me H 8.585 7.987 36 O

N-Morpholino

3,5-Dimethylbenzyl Et Me H 6.763 <4 37 O NMe2

2,5-Dimethylbenzyl Et Me H 6.796 5.729 38 O NMe2

3,5-Difluorobenzyl Et Me H 8.155 7.402 39 O NH2

3-Chlorobenzyl Et Me H 5 4.751 40 O NMe2

3-Chlorobenzyl Et Me H 8.585 7.412 41 O NH2

3-Fluorobenzyl Et Me H 5.131 4.473 42 O NMe2

3-Fluorobenzyl Et Me H 8.569 7.18 43 O NMe2

Chemistry 280 Et Me H 7.377 6.422 44 O NMe2

Chemistry 286 Et Me H 7.889 6.355 45 O NMe2

3,5-Dimethylbenzyl Et Me Et 5.519 4.095 46 O NHMe

3,5-Dimethylbenzyl Et Me H 8.119 7.034 47 O

Chemistry 303

3,5-Dimethylbenzyl Et Me H 7.767 6.968 48 O NMe2

Chemistry 310 Et Me H 8 6.711 49 O NH2

Chemistry 316 Et Me H <4 <5 50 O NH2

3-Trifluoromethylbenzyl Et Me H <5 <5 51 O NH2

Chemistry 334 Et Me H 5.384 <5 52 O NH2

4-Trifluoromethylbenzyl Et Me H <4 <5 53 O NMe2

4-Trifluoromethylbenzyl Et Me H 5.828 <5 54 O NH2

4-Chlorobenzyl Et Me H <4 <5 55 O NMe2

4-Chlorobenzyl Et Me H 6.651 56 O

Chemistey 363

3,5-Dimethylbenzyl Et Me H 8.194 7.11 57 O NMe2

3-Trifluoromethylbenzyl Et Me H 8.066 6.414 58 O NH2

2,4,6-Trimethylbenzyl Et Me H <4 <5 59 O NMe2

2,4,6-Trimethylbenzyl Et Me H 5.029 <5 60 O NMe2

3-Bromobenzyl Et Me H 8.444 7.001 61 O

Chemistry 393

3,5-Dimethylbenzyl Et Me H 7.693 5.922 62 O

Chemistry 399

3,5-Dimethylbenzyl Et Me H 6.604 5.305 63 O NMe2

3,5-Dimethylbenzyl Me n-Pr H 7.029 6.334 64 O NHC(═O)i-Pr

3,5-Dimethylbenzyl Et Me H 65 O NMe2

2-Chlorobenzyl Et Me H 8.284 6.405 66 O NMe2

Chemistry 430 Et Me H 7.588 5.72 67 O

Chemistry 435

3,5-Dimethylbenzyl Et Me H 6.804 4.955 68 O

Chemistry 441

3,5-Dimethylbenzyl Et Me H 69 O NH(n-Bu)

3,5-Dimethylbenzyl Et Me H 6.891 5.655 70 O NMe2

3,5-Dimethylbenzyl

Chemistry 45 Me H 7.752 7.159 71 O NMe2

3,5-Dimethylbenzyl n-Pr Me H 7.777 7.049 72 O

Chemistry 485

3,5-Dimethylbenzyl Et Me H 7.079 <4 73 O NH2

Chemistry 472 Et Me H 8.027 6.92 74 O NH2

Chemistry 476 Et Me H <4 <4 75 O NMe2

Chemistry 490 Et Me H 5.252 4.132 76 O NH2

3,5-Dimethylbenzyl H i-Am H <5.494 <4 77 O NMe2

3,5-Dimethylbenzyl H i-Am H 5.827 <4 78 O

Chemistry 507

3,5-Dimethylbenzyl Et Me H 8.678 7.128 79 O

Chemistry 513

3,5-Dimethylbenzyl Et Me H 6.987 5.47 80 O NH2

Chemistry 520 Et Me H <4 <4 81 O NHEt

3,5-Dimethylbenzyl Et Me H 7.866 6.444 82 O

Chemistry 531

3,5-Dimethylbenzyl Et Me H 7.735 5.813 83 O NH2

Chemistry 538 Et Me H <4.033 <4 84 O NH2

Chemistry 544 Et Me H <4 <4 85 O NH2

3-Methylbenzyl Me Me H 4.954 <4 86 O NH2

3-Methylbenzyl Et Me H 7.863 5.936 87 O NH2

3-Methylbenzoyl Et Me H 6.46 5.653 88 O NMe2

Chemistry 568 Et Me H <4 89 O NMe2

3,5-Dimethylbenzyl H n-Bu H 6.237 90 O NMe2

3,5-Dimethylbenzyl H n-Bu H 6.359 91 O NH2

3-Methylbenzyl (CH2)4 (CH2)4 H 5.73 92 O NMe2

3-Methylbenzyl (CH2)4 (CH2)4 H 7.807 93 O NMe2

3-Methylbenzoyl Et Me H 8.721 94 O NH2

3-Methylbenzoyl Me Me H 5.153 95 O NEt2

3-Methylbenzoyl Et Me H 8.268 96 O NMe2

3-Methylbenzoyl Me Me H 7.824 6.37 97 O NH2

Chemistry 622 Et Me H <4 <4 98 O NH2

3-Ethylbenzyl Et Me H 5.358 4.578 99 O NMe2

3-Ethylbenzyl Et Me H 8.569 6.718 100 O NH2

3,5-Dimethylbenzyl H Me H 4.871 <4 101 O NMe2

3,5-Dimethylbenzyl H Me H 6.341 4.25 102 O NMe2

Chemistry 652 Et Me H 4.369 <4 103 O NH2

Chemistry 658 Et Me H 5.747 104 O NMe2

Chemistry 664 Et Me H 8 7.058 105 O NH2

3,5-Dimethylbenzyl Cl H H 4.943 106 O NMe2

3,5-Dimethylbenzyl Cl H H 7.063 107 O NMe2

3-Methylbenzoyl (CH2)4 (CH2)4 H 7.231 108 O NMe2

3-Methylbenzoyl Me Et H 7.005 109 O

Chemistry 699

3,5-Dimethylbenzyl H OMe H 110 O NMe2

Chemistry 706 Et Me H 7.783 111 O NH2

Chemistry 712 Et Me H <4 112 O NMe2

Chemistry 718 Et Me H 6.394 113 O NH2

Chemistry 724 Et Me H 5.273 114 O

Chemistry 729

Chemistry 730 Et Me H 115 O NMe2

3-Methylbenzoyl Et Me

Chemis- try 745 <4.307 116 O NMe2

Chemistry 748 Et Me H 6.627 117 O CH2NMe2

3-Methylbenzyl (CH2)4 (CH2)4 H <4.139 118 O NH2

3-Dimethylbenzyl Me i-Pr H 4.042 119 O NMe2

3-Dimethylbenzyl Me i-Pr H 6.114 120 O NH2

3-Methoxybenzyl Et Me H 5.033 121 O NMe2

3-Methoxybenzyl Et Me H 8.469 6.948 122 O NMe2

3-OHbenzyl Et Me H 7.196 123 O

Chemistry 789

3,5-Dimethylbenzyl Et Me H 8.444 6.918 124 O NH2

Chemistry 796 Et Me H 4.389 125 O NHCHO

3-Methylbenzyl Et Me H 126 O NHCHO

3-Methylbenzoyl Et Me H 127 O NMe2

Chemistry 814 Et Me H 4.174 128 O NMe2

Chemistry 820 Et Me H 7.848 129 O

Chemistry 825

3,5-Dimethylbenzyl Et Me H 8.398 7.057 130 O NH2

Chemistry 832 Et Me H <4 131 O NH2

3-Methylbenzyl (CH2)3 (CH2)3 H 5.799 132 O NMe2

3-Methylbenzyl (CH2)3 (CH2)3 H 7.863 133 O NMe2

Chemistry 850 Et Me H 4.94 134 O NH2

Chemistry 856 Et Me H 4.056 135 O NMe2

Chemistry 862 Et Me H 6.688 136 O

3-Methylbenzyl Et Me H 9 6.996 137 S NMe2

3,5-Dimethylbenzyl Et Me H 7.658 138 S NMe2

3,5-Dimethylbenzoyl Et Me H 8.215 7.401 139 O NHMe

3-Trifluoromethylbenzyl Et Me H 6.908 140 O NH2

3-Trifluoromethylbenzoyl Et Me H 5.766 141 O NH2

Chemistry 898 Et Me H 4.642 142 O NH2

3-Methylbenzoyl (CH2)3 (CH2)3 H 4.869 143 O NMe2

Chemistry 910 Et Me H 7.421 144 O

Chemistry 915

3-Methylbenzyl Et Me H 6.446 145 O

Chemistry 921

3-Methylbenzyl Et Me H 8.42 6.028 146 O

Chemistry 927

Chemistry 928 Et Me H 147 O NMe2

Chemistry 934 Et Me H 7.721 148 O NMe2

3-Methylbenzoyl (CH2)3 (CH2)3 H 7.863 149 O NMe2

Chemistry 946 Et Me H 8.959 7.883 150 O NH2

Chemistry 952 Et Me H 4.881 151 O NMe2

Chemistry 958 Et Me H 7.845 152 O NMe2

3,5-Dimethylbenzyl Et Me Ph 4.21 153 O NMe2

3,5-Dimethylbenzyl Et Me NH2 6.749 154 O

Chemistry 981

3-Methylbenzyl Et Me H 8.009 6.262 155 O

Chemistry 987

3-Methylbenzyl Et Me H 7.514 156 O NH2

Chemistry 994 Et Me H 4.934 157 O NMe2

Chemistry 1000 Et Me H 6.413 158 O NMe2

Chemistry 1006 Et Me H 8.041 6.625 159 O NH2

Chemistry 1012 Et Me H 7.011 160 O NMe2

Chemistry 1018 Et Me H 8.678 7.177 161 O

Chemistry 1023

3-Trifluoromethylbenzyl Et Me H 7.821 5.814 162 O NMe2

Chemistry 1030 Et Me H 6.418 5.026 163 O NMe2

Chemistry 1036 Et Me H 5.596 4.236 164 O

Chemistry 1041

3-Methylbenzyl Et Me H 7.818 6.505 165 O NMe2

Chemistry 1048 Et Me H 4.354 <4 166 O NMe2

Chemistry 1054 Et Me H 5.693 4.518 167 O NMe2

Chemistry 1060 Et Me H 6.338 5.828 168 O NH2

Chemistry 1066 Et Me H 4.525 4.806 169 O NMe2

Chemistry 1072 Et Me H 7.101 5.771 170 O NMe2

Chemistry 1078 Et Me H 8.553 7.224 171 O NMe2

Chemistry 1084 Et Me H 5.895 4.74 172 O NH2

3,5-Dimethylbenzyl (CH2)4 (CH2)4 H 6.419 4.903 173 O NMe2

3,5-Dimethylbenzyl (CH2)4 (CH2)4 H 8.086 6.489 174 O NMe2

3-Bromobenzoyl Et Me H 8.921 7.68 175 O

Chemistry 1107

3-Methylbenzoyl Et Me H 8.921 7.717 176 O NMe2

Chemistry 1114 Et Me H 8.432 6.436 177 O NH2

Chemistry 1120 Et Me H 5.106 <4 178 O NMe2

Chemistry 1126 Et Me H 7.873 6.461 179 O NHMe

3-Bromobenzoyl Et Me H 8.42 7.182 180 O

Chemistry 1137

3-Methylbenzyl Et Me H 5.988 181 O NMe2

Chemistry 1150 Et Me H 7.928 182 O NH2

Chemistry 1156 Et Me H 5.933 183 O NMe2

Chemistry 1162 Et Me H 8.481 184 O

Chemistry 1167

3-Bromobenzyl Et Me H 8.523 6.804 185 O

Chemistry 1173

3-Bromobenzoyl Et Me H 8.745 7.433 186 O NH2

Chemistry 1180 Et Me H 5.781 187 O NMe2

Chemistry 1186 Et Me H 8.481 7.006 188 O NH2

Chemistry 1192 Et Me H 7.063 189 O NH2

3,5-Dichlorobenzyl Et Me H 6.401 190 O NH2

3,5-Dichlorobenzyl Et Me H 7.757 191 O NMe2

3,5-Dichlorobenzyl Et Me H 8.097 7.553 192 O NMe2

3,5-Dichlorobenzyl Et Me H 8.699 8.319 193 O NMe2

Chemistry 1222 Et Me H 8.481 7.245 194 O NH2

Chemistry 1228 Et Me H 4.665 195 O

Chemistry 1233

3-Methylbenzyl Et Me H 8.569 6.52 196 O NMe2

Chemistry 1240 Et Me H 6.411 197 O NH2

Chemistry 1246 Et Me H 7.307 198 O NH2

Chemistry 1252 Me H H 4.457 199 O

Chemistry 1257

3-Methylbenzyl Et Me H 7.924 200 O

Chemistry 1263

Benzyl Et Me H 8.42 5.95 201 O NMe2

Chemistry 1276 Et Me H 8.585 7.231 202 O NH2

2-Bromobenzyl Et Me H 5.715 203 O NMe2

2-Bromobenzyl Et Me H 8.161 

1. A compound having the formula (1)

wherein: Q represents —NR₁R₂ or —R₀NR₁R₂ wherein: R₀ represents C₁₋₆ alkanediyl; R₁ and R₂ each independently represent C₁₋₆alkyl or C₃₋₆alkenyl; said C₁₋₆alkyl and C₃₋₆alkenyl may be substituted with one, two or three substituents selected from hydroxy, C₁₋₄alkyloxy, C₁₋₄alkylthio, aryloxy, arylthio, amino, mono- or di(C₁₋₄alkyl)amino and aryl; or R₁ and R₂ taken together may form a bivalent radical —R₁-R₂— wherein —R₁-R₂ — represents —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—NR₇—(CH₂)₂, —(CH₂)₂—CH(NHR₇)—(CH₂)₂— or —(CH₂)_(n) wherein R₇ represents hydrogen or C₁₋₄alkyl and n represents 2, 3, 4, 5 or 6; R₃ represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl, R₄ and R₅ each independently represent hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl, C₁₋₄alkoxy, C₁₋₄alkyloxyC₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl) amino, formyl, C₁₋₄alkylcarbonyl carboxyl, C₁₋₄ alkyloxycarbonyl, or C₁₋₄alkyl aminocarbonyl; wherein C₁₋₆alkyl and C₃₋₆alkenyl may be substituted with one, two or three substituents selected from hydroxy, C₁₋₄alkyloxy, C₁₋₄alkyl thio, aryloxy, arylthio, amino, mono- or di(C₁₋₄alkyl)amino and aryl; or R₄ and R₅ taken together form a bivalent radical of formula —R₄-R₅— wherein —R₄-R₅— represents —CH═CH—CH═CH— or —(CH₂)_(t), wherein t represents 3 or 4; R₆represents hydrogen, hydroxy, C₁₋₄alkyloxy, c₁₋₆alkyl, C₃₋₆alkenyl, aryl, C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino or alkylaryl; Y represents O or S; X represents a radical of formula: —(CH₂)_(p)   (a) or —(CH₂)_(q)—Z—(CH₂)_(r)   (b) wherein p represents 1, 2, 3, 4 or 5; q represents 0, 1, 2, 3, 4 or 5; r represents 0, 1, 2 or 3; Z represents NR₈, C(═O), CHOH, CHNR₈R₉; CF₂, O, S or CH═CH; wherein R₈ and R₉ each independently represent hydrogen or C₁₋₄ alkyl; or a N-oxide, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof.
 2. A compound according to claim 1 wherein R₁ and R₂ represent each a methyl group.
 3. A compound according to claim 1 wherein X represents —CH₂— and R₃ represents a phenyl group substituted with two methyl groups.
 4. A compound according to claim 1 which is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.
 5. A process for the obtention of compounds according to claim 1 wherein X represents —CH₂—, Y represents O, R₃ is an optionally phenyl group substituted and R₆ is hydrogen comprising the following steps: a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, resulting in a lithiated derivate of the said pyridine. b) transforming said lithiated derivate into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide. c) obtaining a protected pyridinone by reacting the organocopper reagent with optionally substituted benzyl halide. d) hydrolysing said protected pyridinone and obtaining a deprotected pyridinone. e) substituting the amine-3 group of said deprotected pyridinone and obtaining the desired pyridinone compound.
 6. A process for the obtention of compounds according to claim 1 wherein X represents —C(═O), Y represents O, R₃ is an optionally substituted phenyl group, and R₆ is hydrogen wherein: a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C₁-C₆ alkyllithium, resulting in a lithiated derivate of said pyridine. b) reacting the lithiated derivative with an optionally substituted benzaldehyde, resulting in a substituted pyridinone, c) oxidizing said substituted pyridinone, resulting in a protected pyridinone, d) deprotecting said protected pyridinone by hydrolysis, resulting in the desired pyridinone compound.
 7. Lithiated derivative having the following formula:

wherein R₄ and R₅ are as defined in claim 1, and R₁₀ and R₁₁ are independently C₁-C₆ alkyl.
 8. Pharmaceutical compositions comprising a therapeutically effective amount of at least a compound according to claim 1 and pharmaceutical carriers.
 9. Method of treatment of HIV-related diseases comprising the administration of an effective amount of a compound according to claim
 1. 10. Method of treatment of HIV-infection comprising the administration of an effective amount of a compound according to claim
 1. 